Combined autophagy and HDAC inhibition A phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors
Combined autophagy and HDAC inhibition A phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors
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DOI：
10.4161/auto.29231
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发表时间：
2014-08-01
期刊：
影响因子：
13.3
通讯作者：
Carew, Jennifer S.
中科院分区：
文献类型：
--
作者：
Mahalingam, Devalingam;Mita, Monica;Carew, Jennifer S.
我们先前报道了抑制自噬通过组织蛋白酶D介导的机制显著增强组蛋白去乙酰化酶（HDAC）抑制剂伏立诺他（VOR）的抗癌活性。因此，我们进行了一项首次人体研究，以研究自噬抑制剂羟氯喹（HCQ）和VOR联合治疗晚期实体瘤患者的安全性、初步疗效、药代动力学（PK）和药效学（PD）。在研究中接受治疗的27例患者中，24例被认为可完全评价研究评估和毒性。患者口服递增剂量的HCQ每日（QD）（21天周期的第2天至第21天）与400 mg VOR QD（第1天至第21天）联合治疗。治疗相关不良事件（AE）包括1 - 2级恶心、腹泻、疲乏、体重减轻、贫血和肌酐升高。在少数患者中观察到3级疲乏和/或骨髓抑制。疲乏和胃肠道AE为剂量限制性毒性。600毫克HCQ和400毫克VOR被确定为最大耐受剂量和推荐的II期方案。1例肾细胞癌患者证实了持久部分缓解，2例结直肠癌患者的疾病长期稳定。添加HCQ未显著影响VOR的PK特征。肿瘤活检组织中CDKN 1A和CTSD表达的治疗相关增加比外周血单核细胞更明显。基于这种组合的安全性和初步疗效，目前正在计划进行额外的临床研究，以进一步研究自噬抑制作为增加HDAC抑制剂疗效的新方法。
We previously reported that inhibition of autophagy significantly augmented the anticancer activity of the histone deacetylase (HDAC) inhibitor vorinostat (VOR) through a cathepsin D-mediated mechanism. We thus conducted a first-in-human study to investigate the safety, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of the combination of the autophagy inhibitor hydroxychloroquine (HCQ) and VOR in patients with advanced solid tumors. Of 27 patients treated in the study, 24 were considered fully evaluable for study assessments and toxicity. Patients were treated orally with escalating doses of HCQ daily (QD) (d 2 to 21 of a 21-d cycle) in combination with 400 mg VOR QD (d one to 21). Treatment-related adverse events (AE) included grade 1 to 2 nausea, diarrhea, fatigue, weight loss, anemia, and elevated creatinine. Grade 3 fatigue and/or myelosuppression were observed in a minority of patients. Fatigue and gastrointestinal AE were dose-limiting toxicities. Six-hundred milligrams HCQ and 400 mg VOR was established as the maximum tolerated dose and recommended phase II regimen. One patient with renal cell carcinoma had a confirmed durable partial response and 2 patients with colorectal cancer had prolonged stable disease. The addition of HCQ did not significantly impact the PK profile of VOR. Treatment-related increases in the expression of CDKN1A and CTSD were more pronounced in tumor biopsies than peripheral blood mononuclear cells. Based on the safety and preliminary efficacy of this combination, additional clinical studies are currently being planned to further investigate autophagy inhibition as a new approach to increase the efficacy of HDAC inhibitors.